arbekacin (NPC-14) / Nobelpharma - LARVOL DELTA

Total syntheses of ent-aogacillin A and aogacillin B. (PubMed, Chem Sci) - "Aogacillins A and B, circumventors of arbekacin resistance in MRSA, possess a densely oxidized spirolactone moiety and an electron deficient terminal exocyclic double bond...A new strategy is proposed and successfully implemented, which features allylic C-H oxidation and a one-pot sequential aldol reaction and lactonization. This enables us to achieve the first and asymmetric total synthesis of aogacillin B and ent-aogacillin A in 7 steps."

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Drug repurposing for type 2 diabetes: computational studies of potential alpha-glucosidase inhibitors from DrugBank. (PubMed, In Silico Pharmacol) - "We selected 10 compounds with top docking performance, and rescoring these compounds with MMGBSA calculations produced arbekacin, neamine, and sisomicin with a binding free energy of - 72.13, - 55.14, and - 69.07 kcal/mol, respectively, as the top three compounds. These compounds were subsequently analysed and compared with the standard drug, acarbose for their protein-binding stability using molecular dynamics simulation (MDS) approach. The MDS analysis suggests that sisomicin exhibited the most stable interactions and stronger post-MDS binding free energy with alpha-glucosidase. These findings suggest that sisomicin is a potential inhibitor of alpha-glucosidase, and a novel candidate for drug repurposing in antidiabetic therapy."

Journal • Diabetes • Metabolic Disorders • Type 2 Diabetes Mellitus • MGAM

Multi-model-based validation of multi-environment trial results in horse gram (Macrotyloma uniflorum Lam. Verdc.). (PubMed, Sci Rep) - "The selection differential analysis affirms the superiority of these genotypes for the tested traits (NC-25.70%, NPC-14.20%, NP-28.80%, NS-9.94%, YD-30.40%, & DM-0.05%). In conclusion, the validation METs reveal a slight variation among the findings between fixed and random effect models, emphasising the importance of integrating multiple analytical approaches for an effective GEI analysis in horse gram."

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Structure-function comparison of Arbekacin with other aminoglycosides elucidates its higher potency as bacterial translation inhibitor. (PubMed, Sci Rep) - "Our 3.1 Å resolution cryo-EM structure of ABK-bound ribosome containing mRNA and initiator-tRNA, shows interactions of the unique AHB moiety of ABK with rRNA nucleobases, which likely provide additional stabilization of ABK at the canonical aminoglycoside binding pocket and contribute to its prolonged dwelling time. Our structural and functional analyses provide molecular basis for higher potency of ABK in bacterial translation inhibition and opens the possibility of rational design of new antibiotics."

Clinical • Journal

Last general practitioner consultation during the final month of life: a national medical record review of suicides in Sweden. (PubMed, BMC Prim Care) - "The National Cause of Death Register has excellent coverage of suicide deaths and access to medical records was very good. The medical record review provided detailed information regarding primary care utilization before death by suicide. Because of the lack of statistical power, due to the limited number of persons with GP contact during the last month of life, we chose not to correct for multiple comparisons. Our study approach did not capture the reasons behind GPs' documentation of elevated suicide risk. No systematic inter-rater reliability (IRR) testing was made, however, reviewers received training and continuous support from the research group."

Journal • Review • Cardiovascular • Psychiatry

Experimental Determination of the pKa Values of Clinically Relevant Aminoglycoside Antibiotics: Toward Establishing pKa-Activity Relationships. (PubMed, ACS Omega) - "In this work, we measured the pKa values for individual amino groups of the six clinically relevant aminoglycoside antibiotics gentamicin, tobramycin, amikacin, arbekacin, plazomicin, and apramycin using 15N-1H heteronuclear multiple-bond correlation and 1H NMR experiments. These pKa values were used to calculate the net charges of the aminoglycosides and the protonation levels of amino groups under various pH conditions. The results were analyzed in relation to the mode of interaction and inhibition to establish pKa relationships for rRNA binding, inhibitory activity, and the pH dependence of the uptake into bacterial cells."

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Direct visualization of ribosomes in the cell-free system revealed the functional evolution of aminoglycoside. (PubMed, J Biochem) - "Furthermore, with the direct link to biochemical analysis at the same condition as cryo-EM observation, we revealed the evolution of 2-DOS aminoglycosides from dibekacin (DBK) to arbekacin (ABK) by acquiring the synthetic tailored anchoring motif to lead to stronger binding affinity to ribosomes. Our cryo-EM structures of DBK and ABK bound ribosomes in the cell-free environment clearly depicted a synthetic tailored γ-amino-α-hydroxybutyryl (HABA) motif formed additional interactions with the ribosome enhancing antibiotic bindings. This new approach would be valuable for understanding the function of antibiotics for more efficient drug development."

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Improved characterization of aminoglycoside penetration into human lung epithelial lining fluid via population pharmacokinetics. (PubMed, Antimicrob Agents Chemother) - "The area under the curve in ELF vs plasma ranged from 50% to 100% and equilibration half-lives from 0.61 to 5.80 h, indicating extensive system hysteresis. Aminoglycoside ELF peak concentrations were blunted, but overall exposures were moderately high."

Journal • PK/PD data • Infectious Disease • Respiratory Diseases

A Comparison of the Minimum Inhibitory Concentration of Antibiotics in Staphylococcus Species Isolated From Orthopedic and Respiratory Medicine Infections. (PubMed, Cureus) - "The VCM MICs of Staphylococcus species from orthopedic infections were higher than those of respiratory samples, particularly MRCNS from implant-related samples."

Journal • Infectious Disease • Orthopedics

Basis for aminoglycoside evasion of bacterial antibiotic resistance arising from ribosomal RNA modification (NACFC 2023) - "When the m7 G1405 modification is present, all 4,6-deoxystreptamine (4,6-DOS)- containing aminoglycosides are rendered ineffective, including the latest generation of drugs (e.g., plazomicin)...We also present high-resolution cryo-electron microscopy structures of m1 A1408-modified 70S ribosomes in complex with arbekacin and geneticin, providing detailed structural insights into the binding of these aminoglycosides as they evade the m1A1408 modification... Our study provides a fundamental basis for comprehending molecular-level interactions between aminoglycosides and methylated rRNA. This understanding could aid in development of new aminoglyco-side derivatives that can combat pathogens with aminoglycoside-resist-ance rRNA methyltransferases and of aminoglycosides with reduced toxicity using similar strategies."

Infectious Disease • Nephrology • Respiratory Diseases

Effects of thiram exposure on liver metabolism of chickens. (PubMed, Front Vet Sci) - "Metabolomics analysis shows that 62 metabolites were down-regulated (ginsenoside F5, arbekacin, coproporphyrinogen III, 3-keto Fusidic acid, marmesin, isofumonisin B1, 3-Hydroxyquinine, melleolide B, naphazoline, marmesin, dibenzyl ether, etc.) and 35 metabolites were up-regulated (tetrabromodiphenyl ethers, deoxycholic acid glycine conjugate, L-Palmitoylcarnitine, austalide K, hericene B, pentadecanoylcarnitine, glyceryl palmitostearate, quinestrol, 7-Ketocholesterol, tetrabromodiphenyl ethers, etc.) in thiram-induced chickens, mainly involved in the metabolic pathways including glycosylphosphatidylinositol (GPI)-anchor biosynthesis, porphyrin and chlorophyll metabolism, glycerophospholipid metabolism, primary bile acid biosynthesis and steroid hormone biosynthesis. Taken together, this research showed that thiram exposure significantly altered hepatic metabolism in chickens. Moreover, this study also provided a basis for regulating the use and disposal of thiram to..."

Journal • Metabolic Disorders

Aprosamine Derivatives Active against Multidrug-Resistant Gram-Negative Bacteria. (PubMed, ACS Infect Dis) - "All 8'-β-glycosylated aprosamine derivatives (3a-h) showed excellent antibacterial activity against carbapenem-resistant Enterobacteriaceae and 16S ribosomal RNA methyltransferase-producing multidrug-resistant Gram-negative bacteria compared to the clinical drug, arbekacin. In particular, 8b and 8h showed approximately 2- to 8-fold antibacterial activity against carbapenem-resistant Enterobacteriaceae and 8- to 16-fold antibacterial activity against resistant Gram-positive bacteria, such as methicillin-resistant Staphylococcus aureus and vancomycin-resistant enterococci, compared to apramycin. Our results showed that aprosamine derivatives have immense potential in the development of therapeutic agents for multidrug-resistant bacteria."

Gram negative • Journal • Infectious Disease

The synergetic effect of sitafloxacin-arbekacin combination in the Mycobacterium abscessus species. (PubMed, Sci Rep) - "Out of 34 MABS, 8 strains treated with sitafloxacin-amikacin combination, 9 of sitafloxacin-imipenem combination, 19 of sitafloxacin-arbekacin combination, and 9 of sitafloxacin-clarithromycin combination showed synergistic effects, respectively. We demonstrated the synergistic effect of the sitafloxacin-arbekacin combination against MABS. Further, this combination regimen might be more effective against Mab or rough morphotypes of MABS."

Journal • Infectious Disease

Arbekacin-Loaded Inhalable Nanocomposite Particles Specific to Pseudomonas aeruginosa Prepared Using a Two-Solution Mixing-Type Spray Nozzle. (PubMed, Biol Pharm Bull) - "The aerosol performance of ABK-SD/MAN nanocomposite particles was superior to that of ABK-MAN microparticles in terms of the fine particle fraction (28.4 ± 5.4%, ABK-SD/MAN nanocomposite particles; 11.4 ± 7.6%, ABK-MAN microparticles). These results suggest that ABK-SD/MAN nanocomposite particles are suitable for use in inhalation drug formulations and useful for the treatment of lung infections involving Pseudomonas aeruginosa."

Journal • Infectious Disease • Pneumonia • Respiratory Diseases

Analysis of impurity profiling of arbekacin sulfate by ion-pair liquid chromatography coupled with pulsed electrochemical detection and online ion suppressor-ion trap-time off light mass spectrometry. (PubMed, J Pharm Biomed Anal) - "Previously reported approaches such as two-dimensional (2D)LC were hardly applicable in this case due to the lack of ultraviolet (UV) absorbing chromophores in ABK and its impurities. The sodium hydroxide solution was replaced by aqueous ammonia to adjust the pH of the mobile phase used in LC-PED. The other challenge encountered was the ion suppression effect caused by trifluoroacetic acid (TFA) and pentafluoroproponic acid (PFPA) in the mobile phase. Some strategies such as "TFA-fixed" and its modifications were tried, but they were inconvenient and severe contamination of the MS was observed. A cationself-regenerating suppressor (CSRS), which was originally designed for increasing analyte conductivityof ammonia and amines analysis in ion chromatography (IC), was coupled between the LC and Ion Trap-Time of Flight (IT-TOF)-MS and almost all TFA and PFPA in the mobile phase were removed. The limit of..."

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Stenotrophomonas maltophilia from Nepal Producing Two Novel Antibiotic Inactivating Enzymes, a Class A β-Lactamase KBL-1 and an Aminoglycoside 6'-N-Acetyltransferase AAC(6')-Iap. (PubMed, Microbiol Spectr) - "coli transformants expressing aac(6')-Iap were less susceptible to arbekacin, amikacin, dibekacin, isepamicin, neomycin, netilmicin, sisomicin and tobramycin. The recombinant AAC(6')-Iap protein acetylated all aminoglycosides tested, except for apramycin and paromomycin...Genetic backgrounds of most S. maltophilia strains in Nepal were similar to those in European countries. Surveillance of drug-resistant S. maltophilia in medical settings in Nepal is necessary."

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Comparing the pharmacokinetics and organ/tissue distribution of anti-methicillin-resistant Staphylococcus aureus agents using a rat model of sepsis. (PubMed, Xenobiotica) - "In this study, we evaluated and compared the pharmacokinetics of methicillin-resistant Staphylococcus aureus treatment agents in sepsis with that of vancomycin, arbekacin, linezolid, and daptomycin.Rat models of sepsis were prepared using cecal ligation puncture. In contrast, the distribution of linezolid from the blood to the organs/tissues in septic rats was comparable to that in normal rats.Sepsis-induced nephrotoxicity results in the stasis of vancomycin in the kidney, suggesting that this exacerbates proximal tubular epithelial cell injury. No dose modification of linezolid may be required for patients with sepsis."

Journal • PK/PD data • Preclinical • Infectious Disease • Septic Shock

Target Therapeutic Ranges of Anti-MRSA Drugs, Linezolid, Tedizolid and Daptomycin, and the Necessity of TDM. (PubMed, Biol Pharm Bull) - "The target therapeutic ranges of vancomycin, teicoplanin, and arbekacin have been determined, and therapeutic drug monitoring (TDM) is performed in clinical practice...To secure its safety, C (<20 µg/mL) monitoring is important. Therefore, TDM is necessary."

Journal • Gastrointestinal Disorder • Infectious Disease • Pneumonia • Respiratory Diseases

A study of trends and factors associated with therapeutic drug monitoring (TDM) implementation for arbekacin treatment using a large Japanese medical claims database. (PubMed, J Infect Chemother) - "From 2010 to 2019, the proportion of TDM implementation for ABK was significantly low. Moreover, the factors associated with TDM implementation were clarified. An environment wherein pharmacists can help implement TDM for patients receiving ABK would be beneficial."

Journal • Infectious Disease • Pneumonia • Respiratory Diseases • Septic Shock

Clinical Efficacy and Safety of Arbekacin against Pneumonia in Febrile Neutropenia: A Retrospective Study in Patients with Hematologic Malignancies. (PubMed, Infect Chemother) - "The present study demonstrated that ABK is effective and safe in patients with FN and concurrent pneumonia caused by antimicrobial-resistant Gram-positive cocci. ABK may also be effective in patients who are unresponsive to other anti-MRSA drugs. Therefore, ABK may be beneficial in the treatment of pneumonia caused by antimicrobial-resistant Gram-positive cocci in patients with FN."

Journal • Retrospective data • Acute Kidney Injury • Febrile Neutropenia • Hematological Disorders • Hematological Malignancies • Infectious Disease • Nephrology • Neutropenia • Oncology • Pneumonia • Renal Disease • Respiratory Diseases

A multidrug-resistant Stenotrophomonas maltophilia clinical isolate from Kamuzu Central Hospital, Malawi. (PubMed, Malawi Med J) - "A ceftriaxone and meropenem nonsusceptible isolate (Sm-MW08), recovered in December 2017 at KCH, was referred to the National Microbiology Reference Laboratory for identification...Sm-MW08 was identified as S. maltophilia and exhibited resistance to a range of antibiotics, including all β-lactams, aminoglycosides (except arbekacin), chloramphenicol, minocycline, fosfomycin and fluoroquinolones, but remained susceptible to colistin and trimethoprim-sulfamethoxazole...Herein, we have described an MDR S. maltophilia from KCH in Malawi, that was resistant to almost all locally available antibiotics. We therefore recommend the practice of effective infection prevention measures to curtail spread of this organism."

Clinical • Journal • Infectious Disease

Emergence of a multidrug-resistant plasmid encoding bla , bla and armA in a clinical isolate of Acinetobacter variabilis in Japan. (PubMed, J Med Microbiol) - "The isolate was resistant to carbapenems, aminoglycosides and ciprofloxacin, with minimum inhibitory concentrations (MICs) of 32 µg ml for imipenem and meropenem; > 1024 µg ml for amikacin, arbekacin, gentamicin and tobramycin; and 8 µg ml for ciprofloxacin. The isolate was found to harbour a 68-kbp plasmid carrying bla , which encodes New Delhi metallo-β-lactamase-1 (NDM-1); bla , which encodes an OXA-58-like carbapenemase and; armA, which encodes ArmA 16S rRNA methylase conferring pan-aminoglycoside resistance. To our knowledge, this is the first report of a plasmid harbouring the three major drug-resistance genes, bla , bla and armA."

Clinical • Journal

Basic and applied research on multiple aminoglycoside antibiotic resistance of actinomycetes: an old-timer's recollection. (PubMed, J Ind Microbiol Biotechnol) - "Discovery of a novel antibiotic indolizomycin through protoplast fusion treatment between S. tenjimariensis and S. griseus strains with different AGR phenotypes and 6. Double stage-acting activity of arbekacin (ABK; an anti-MRSA semisynthetic AG) discovered by acetylation of ABK with cloned AACs; i.e. both ABK and its acetylated derivatives showed remarkable antibiotic activities."

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Nationwide surveillance of antimicrobial susceptibility of 509 rapidly growing mycobacteria strains isolated from clinical specimens in Japan. (PubMed, Sci Rep) - "We identified 15 RGM species, most of which were susceptible to amikacin and linezolid. The proportion of MAB isolates with MIC ≤ 2 mg/L for rifabutin was significantly higher than that of MMA [MAB: 50/178 (28.1%) vs. MMA: 23/130 (17.7%); p = 0.041]. In summary, our study revealed the antimicrobial susceptibility profile of 15 RGM species isolated in Japan and indicated that arbekacin, sitafloxacin, and rifabutin may be possible therapeutic options for RGM infections."

Clinical • Journal • Complement-mediated Rare Disorders • Infectious Disease

Mechanistic insights into translation inhibition by aminoglycoside antibiotic arbekacin. (PubMed, Nucleic Acids Res) - "Importantly, translocation and termination events cannot be completely stopped even with high ABK concentration. Extrapolating our kinetic model of ABK action, we postulate that aminoglycosides impose bacteriostatic effect mainly by inhibiting translocation, while they become bactericidal in combination with decoding errors."

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